We propose to establish a CDC Prevention Epicenter called, Strategies to Prevent Infection and Reduce Inter-individual Transmission (SPIRIT). Our overall objective is to improve control of transmission of pathogenic microorganisms through advancement of science and practice by improving knowledge about mechanisms of transmission and implementing novel strategies to prevent dissemination of pathogens within healthcare settings. We will direct a broad research portfolio that addresses key challenges in infection prevention across individual, population, and organizational levels. The resources that we bring to the CDC Prevention Epicenter Program will be broadly beneficial to its mission to improve healthcare quality and patient safety. Our work is strongly tied to operational partners and collaborators within the VA, as well as the academic medical centers with which we are affiliated. These connections provide ample access to health systems that will serve as clinical laboratories. We have accumulated the capacity and experience to implement interventions to prevent infection and combat antibiotic resistance across the continuum of care. Moreover, we have developed a computational environment to support comprehensive epidemiological analysis of infections within the Department of Veterans Affairs (VA) Health System. Our research will focus on measurement and modelling of transmission, adherence to personal protective equipment, and regional coordination of control strategies. Knowledge about how patient factors, healthcare practices, and intervention strategies influence transmission is accumulating too slowly to enable nimble responses to emerging threats. Applying new methods of infection modeling to the remarkable electronic data resources that exist within the VA to examine transmission rates of multidrug resistant organisms, we will systematically evaluate these factors and propose efficient, new experiments. Transmission of emerging pathogens such as Ebola and severe acute respiratory syndrome to healthcare workers exposed problems in how health care workers don and doff personal protective equipment (PPE). We will apply methods drawn from adherence engineering to redesign equipment kits to enhance the effective use of PPE across a range of tasks. Regional strategies for infection control have the potential to prevent the spread of emergent pathogens, but face substantial barriers to effective coordinated action. We will address these challenges through implementation of approaches to enhance trust among stakeholders, increase information flow, and support alignment with local and state departments.